PEDIATRIC HYDROXYUREA STUDY GROUP

羟基脲(HU)是一种抗肿瘤药物，已被证明可以 增加胎儿血红蛋白产量的一小部分实验组 患有镰状细胞病(SCD)的成人受试者。因为这些研究 在成人中发现了一种毒性最小的血红蛋白F反应， 一项更大规模的成人疗效安慰剂对照研究是 正在进行中。直到HU疗法对SCD的疗效在 成人试验，没有理由进行大规模的疗效试验 在儿童镰状细胞患者中的试验。然而，有一个小的 全国范围内有多少儿童和青少年有 目前没有可用的治疗方案。这些都是不典型的孩子 伴随着极高的痛苦“危机”发生率，严重复发 胸部综合征或中风的发作，以及无法输血 因为异体免疫。在大多数大型儿科中心，一项试验 的羟基脲将被考虑对这类患者进行一次“同情” 以个人为基础。我们担心的是，尽管这些个人特别 方案可能被证明对治疗个别患者是有益的，将会有 没有获得集体知识，没有组织好的数据可供借鉴 如果到了设计大型前瞻性试验评估的时候 儿童临床疗效观察。在这个提案中，我们组织了一个 儿科临床研究人员联盟，他们将同意不使用 各种特殊方案来治疗他们的病人，但将取而代之的是 遵循一个共同的协议，汇集他们的个人经验。我们有 不打算增加将接受治疗的儿科患者的数量 羟基脲，而是让所有这些患者在一个 举止统一。 已经定义了进入和排除标准。一系列标准 已经开发了数据收集表格。数据协调中心 将设在杜克-北卡罗来纳大学镰刀细胞中心。给药计划和 毒性标准是基于成人经验的结果。 患者将从每天15毫克/公斤开始，以5毫克/公斤的增量递增 每12周一次，遵循严格的毒性标准。最大剂量 将是30毫克/公斤/天。患者将每两周接受一次监测。F 细胞计数将在约翰·霍普金斯医疗中心集中确定 医学博士乔治·多佛所著的《学校》曾表示，最大耐受量是 如果成功，患者将继续服用该剂量12个月。 我们的目标是获得以下问题的初步数据：(1) 羟基脲对提高胎儿血红蛋白水平有效吗？ 儿童，(2)儿童是否有看不到的严重毒性 在成人中，以及(3)羟基脲治疗对生长的影响是什么？ 总体战略将是制定一个共同的剂量计划， 排除标准和监测方案。

Hydroxyurea (HU) is an antineoplastic agent that has been shown to increase fetal hemoglobin production in a small experimental group of adult subjects with sickle cell disease (SCD). Because these studies have revealed a hemoglobin F response with minimal toxicity in adults, a larger-scale, placebo controlled study of efficacy in adults is underway. Until the efficacy of HU therapy for SCD is demonstrated in the adult trial, there is no rationale for doing a large scale efficacy trial in pediatric sickle cell patients. However, there are a small number of children and adolescents around the country for whom there is currently no treatment option available. These are atypical children with exceptionally high rates of painful "crises", severe recurrent episodes of chest syndrome, or stroke, and the inability to be transfused because of alloimmunization. In most large pediatric centers, a trial of hydroxyurea will be considered for such patients on a "compassionate" individual basis. We are concerned that although these individual ad hoc protocols may prove beneficial to treat individual patients, there will be no collective knowledge gained, no organized body of data to draw from if and when it comes time to design a large prospective trial assessing clinical efficacy in children. In this proposal, we organize a consortium of pediatric clinical investigators who will agree not to use a variety of ad hoc protocols to treat their patients, but will instead follow a common protocol and pool their individual experiences. We do not intend to increase the number of pediatric patients who would receive hydroxyurea, but rather to have all of these patients treated in a uniform manner. Entry and exclusion criteria have been defined. A series of standard data collection forms have been developed. The data coordinating center will be based at Duke-UNC Sickle Cell Center. The dosing schedule and toxicity criteria are based on the results of the adult experience. Patients will start on 15 mg/kg/day and be advanced in 5 mg/kg increments every 12 weeks, following strict toxicity criteria. The maximal dose will be 30 mg/kg/day. Patients will be monitored every two weeks. F cell counts will be determined centrally at the Johns Hopkins Medical School by George Dover, M.D. Once the "maximal tolerated dose" is achieved, patients will be continued on that dose for 12 months. Our goal is to obtain preliminary data on the following questions: (1) is hydroxyurea effective in increasing fetal hemoglobin levels in children, (2) are there serious toxicities in children that were not seen in adults, and (3) what is the impact of hydroxyurea therapy on growth? The overall strategy would be to develop a common dosing schedule, exclusion criteria, and monitoring protocol.